Integration of Murine and Human Studies for Mapping Periodontitis Susceptibility.

Periodontitis is one of the most common inflammatory human diseases with a strong genetic component. Due to the limited sample size of available periodontitis cohorts and the underlying trait heterogeneity, genome-wide association studies (GWASs) of chronic periodontitis (CP) have largely been unsuccessful in identifying common susceptibility factors. A combination of quantitative trait loci (QTL) mapping in mice with association studies in humans has the potential to discover novel risk loci. To this end, we assessed alveolar bone loss in response to experimental periodontal infection in 25 lines (286 mice) from the Collaborative Cross (CC) mouse population using micro-computed tomography (µCT) analysis. The orthologous human chromosomal regions of the significant QTL were analyzed for association using imputed genotype data (OmniExpress BeadChip arrays) derived from case-control samples of aggressive periodontitis (AgP; 896 cases, 7,104 controls) and chronic periodontitis (CP; 2,746 cases, 1,864 controls) of northwest European and European American descent, respectively. In the mouse genome, QTL mapping revealed 2 significant loci (-log P = 5.3; false discovery rate = 0.06) on chromosomes 1 ( Perio3) and 14 ( Perio4). The mapping resolution ranged from ~1.5 to 3 Mb. Perio3 overlaps with a previously reported QTL associated with residual bone volume in F2 cross and includes the murine gene Ccdc121. Its human orthologue showed previously a nominal significant association with CP in humans. Use of variation data from the genomes of the CC founder strains further refined the QTL and suggested 7 candidate genes ( CAPN8, DUSP23, PCDH17, SNORA17, PCDH9, LECT1, and LECT2). We found no evidence of association of these candidates with the human orthologues. In conclusion, the CC populations enabled mapping of confined QTL that confer susceptibility to alveolar bone loss in mice and larger human phenotype-genotype samples and additional expression data from gingival tissues are likely required to identify true positive signals.

In vitro testing of venous valves.

The need to test prosthetic venous valves led to the design of a hydraulic mock circuit that reliably mimics natural venous flow. Components of this system simulate calf muscle pump and thoracoabdominal suction pump action. Flow and pressures are serially measured along the circuit. Valve function can be observed and videotaped. Evaluation of biologic venous valves provides visual and quantitative assessment of venous valve function with respect to tissue processing, valve design, and implantation technique. Further improvement in this system in terms of more compliance and less rigidity of components is being pursued.

Psychosocial profile of the parasuicidal patient in Kuwait.

A consecutive sample of 92 parasuicides aged 14-44 years (mean age +/- standard deviation, 22.9 +/- 5.6) was seen during the period December 1984-November 1985 at Kuwait's main teaching general hospital (catchment area 449000 population). Self-poisoning accounted for 85.9%. Their sociodemographic characteristics were consistent with contemporary trends of parasuicidal behaviour reported in other countries. The structure of the Kuwaiti population is quite special. The majority (58.3%) are expatriates mostly males at the working age group while the minority (41.7%) are Kuwaiti nationals. Family discord was the dominant antecedent life event in Kuwaitis. On the other hand, non-Kuwaiti Arabs and non-Arab expatriates reported an excess of work-related problems as precipitating factors. Non-Arab females resorted to more violent methods than other females. Acute situational distress was the most common diagnosis while depression was present in about 25% of the total sample. The attitudes of family members of the parasuicidal patients were discussed in the light of the socio-cultural perspective. Attention to possible preventive measures is suggested. Parasuicide (Kreitman et al 1970) is a topic which has stimulated considerable research in recent years. A wealth of information has become available on the subject and its patterns in different cultures and various countries (WHO 1974). In the "Arab World" a few studies have dealt with parasuicide. El-Islam (1974) studied the characteristics of hospital referred parasuicide in Qatar and indicated that intergenerational conflict was the commonest precipitating life event.(ABSTRACT TRUNCATED AT 250 WORDS)

Onset and progression of experimental bioprosthetic heart valve calcification.

Calcification, the major cause of bioprosthetic heart valve failures, is a serious clinical problem with uncertain pathogenesis. The objectives of the present study were to define the progressive chemical and morphologic sequence of mineralization in glutaraldehyde-treated porcine aortic valve cusps implanted subcutaneously in rats and to compare the pathology and pathophysiology of calcification in subcutaneous implants with that of orthotopic valve replacements in calves. Cusps were implanted subcutaneously in 3-week-old rats for 24 hours to 18 weeks. Cuspal calcium was 114 +/- 18 micrograms/mg of dry weight (mean +/- SEM) at day 21 and 218 +/- 6 at day 56 of implantation and unchanged thereafter. The earliest mineral deposits, noted at 48 hours, were associated with devitalized porcine connective tissue cells, but by 7 days, mineral deposits also involved collagen bundles. Scanning electron microscopy with energy-dispersive x-ray analysis demonstrated predominant accumulation in the spongiosa with a spongiosa to fibrosa energy-dispersive x-ray analysis count ratio of calcium of 15 at 21 days. In stent-mounted glutaraldehyde-preserved porcine valves implanted in five calves as mitral replacements for 69 to 142 days, cuspal calcium was 86 micrograms/mg (mean) (range 47 to 128). Calf implants also had cell oriented and collagen calcification predominating in the valvar spongiosa. In both rat subcutaneous and calf mitral valve models, early diffuse calcific microcrystals evolved into confluent nodules that disrupted tissue architecture. It is concluded that calcification of glutaraldehyde-preserved porcine aortic valves implanted subcutaneously in rats begins within 48 hours, earliest deposits are localized to residual porcine connective tissue cells, but latter deposits also involve collagen fibrils, mineralization is most prominent in the spongiosa, the pathology of calcification in rat subcutaneous implants and calf mitral replacements is comparable, suggesting a common pathophysiology, and calcific nodule formation most likely initiates clinical features.

Techniques for prevention of calcification of valvular bioprostheses.

Calcification of valvular bioprostheses in children is a major problem that has stimulated extensive research in our laboratory. In previous reports, we have shown that the rate of calcification could be reduced by decreasing the phosphate content in the tissue or by blocking calcification binding sites with Mg++ and/or with a surfactant (Tween 80). Since then, we have systematically investigated incorporation of numerous other surfactants and of polyacrylamide within the tissue, and these investigations form the basis of this report. The methods of investigation included subcutaneous implantation of treated tissues in growing rabbits, stability tests, and intracardiac implantation in sheep. Results showed that surfactants differed in their efficacy in mitigating calcification, with N-lauroylsarcosine and triton X-100 being the most efficient. Polyacrylamide incorporation was also efficient in calcification mitigation, but this effect was lost after flexibility testing in vitro or implantation in vivo, a drawback that suggests further research is necessary into stabilization of this polymer. This report not only brings attention to new alternatives in calcification mitigation treatment of bioprosthetic tissues but also underlines important points of methodology.

Calcifications of cardiac valve bioprostheses. Biochemical, histologic, and ultrastructural observations in a subcutaneous implantation model system.

To study the process of calcification in bioprosthesis, 108 glutaraldehyde-treated porcine aortic valve leaflets were implanted subcutaneously in rabbits and removed 1 day to 6 months later; morphologic findings were correlated with biochemically determined levels of calcium (Ca++) and gamma-carboxyglutamic acid (Gla), a vitamin K-dependent Ca++-binding amino acid known to be present in a variety of tissues with pathological calcification. Gla and Ca++ levels began to increase about 2 months after implantation and increased progressively with time. Ca/Gla molar ratios were comparable to those in leaflets of bioprostheses explanted from patients, 22 to 64 months after implantation. Morphologically evident calcification began at the same time that Gla and Ca++ increases were detected biochemically and also increased in severity with time. Electron microscopy showed that calcification primarily involved the surface of collagen fibrils and the interfibrillar spaces. The biochemical and morphological findings in this experimental system are similar to those described in calcified porcine bioprosthetic valve leaflets removed from patients, but occurred much more rapidly. As with pathological calcification of other tissues, progressive calcification was accompanied by increased Gla levels, suggesting that Gla plays a role in the calcification of the leaflets. This model allows rapid comparative evaluation of large numbers of valve leaflets maintained under similar host conditions.